Chalk Drawing by Leonardo da Vinci: The portrait of a man in red chalk in the Royal Library of Turin is widely, though not universally, accepted as a self-portrait of Leonardo da Vinci. It is thought that Leonardo da Vinci drew this self-portrait at about the age of 60. The portrait has been extensively reproduced and has become an iconic representation of Leonardo as a polymath or "Renaissance Man". Despite this, some historians and scholars disagree as to the true identity of the sitter. The portrait is drawn in red chalk on paper. It depicts the head of an elderly man in three-quarter view, his face turned towards the viewer. The subject is distinguished by his long hair and long waving beard which flow over the shoulders and chest. The length of the hair and beard is uncommon in Renaissance portraits and suggests, as now, a person of sagacity.

An acute respiratory disease emerged in Asia before spreading through North Africa and Europe during the first chronicled, inter-regional flu pandemic generally recognized by medical historians and epidemiologists. Influenza-like illnesses had been documented in Europe since at least Charlemagne, with 1357's outbreak the first to be called influenza, but the 1510 flu pandemic is the first to be pathologically described following communication advances brought about by the printing press. Flu became more widely referred to as coqueluche and coccolucio in France and Sicily during this pandemic, variations of which became the most popular names for flu in early modern Europe. The pandemic caused significant disruption in government, church, and society with near-universal infection and a mortality rate of around 1%.

Painting by Raphael: The School of Athens, a fresco by the Italian Renaissance artist Raphael. It was painted between 1509 and 1511 as part of a commission by Pope Julius II to decorate the rooms now called the Stanze di Raffaello in the Apostolic Palace in Vatican City. The fresco depicts a congregation of ancient philosophers, mathematicians, and scientists, with Plato and Aristotle featured in the center. The identities of most figures are ambiguous or discernable only through subtle details or allusions; among those commonly identified are Socrates, Pythagoras, Archimedes, Heraclitus, Averroes, and Zarathustra. Additionally, Italian artists Leonardo da Vinci and Michelangelo are believed to be portrayed through Plato and Heraclitus, respectively. Raphael included a self-portrait beside Ptolemy. Raphael is the only character who is looking directly at the viewer in the artwork. The painting is notable for its use of accurate perspective projection, a defining characteristic of Renaissance art, which Raphael learned from Leonardo; likewise, the themes of the painting, such as the rebirth of Ancient Greek philosophy and culture in Europe were inspired by Leonardo's individual pursuits in theatre, engineering, optics, geometry, physiology, anatomy, history, architecture and art. The School of Athens is regarded as one of Raphael's best-known works and has been described as his "masterpiece and the perfect embodiment of the classical spirit of the Renaissance".

Painting by Albrecht Dürer: Wing of a European Roller, a nature-study watercolor painted from a dead specimen.

Painting by Raphael: The Triumph of Galatea, a fresco painted for the wealthy banker Agostino Chigi's Villa Farnensina

Hieronymus Brunschwygk's book, Liber de arte Distillandi de Compositis, describes medicinal herbs and the construction of stills for processing them.

Painting by Raphael: Madonna della Seggiola, an oil on panel Madonna painting executed c. 1513–1514, and housed at the Palazzo Pitti Collection in Florence, Italy. Although there is documentation on its arrival to its current location, Palazzo Pitti, it is still unknown who commissioned the painting; however, it has been in the Medici family since the 16th century. It depicts Mary embracing the Christ child while sitting in a chair as the young John the Baptist devoutly watches. The Madonna della Sedia is one of the single most important of Raphael's Madonnas. The painting also showcases Raphael's use of the tondo form and his naturalistic approach to depicting the Madonna. The Madonna della Sedia is Raphael's most humanistic form of the Madonna. Throughout Raphael's life, this humanistic representation of the Madonna occupied his mind. The Madonna della Sedia is the incarnation of a realistic mother and child, representing human motherhood. Painted during his Roman period, this Madonna does not have the strict geometrical form and linear style of his earlier Florentine treatments of the same subject. The Madonna is portrayed subtly and naturalistically, including the drapery, her anatomy, and the movement of her body, as if it was a result of an immediate action.

Juan Ponce de León becomes the first European definitely known to sight the modern-day territory of the United States, specifically Florida, mistaking it for another island. He landed somewhere along Florida's east coast, then charted the Atlantic coast down to the Florida Keys and north along the Gulf coast; historian John R. Swanton believed that he sailed perhaps as far as Apalachee Bay on Florida's western coast. Though in popular culture he was supposedly searching for the Fountain of Youth, there is no contemporary evidence to support the story, which most modern historians consider a myth.

Detailed world map produced by Muhiddin Piri (c. 1470–1553), better known as Piri Reis, an Ottoman corsair, navigator, geographer, and cartographer. He is primarily known today for his cartographic works, including his 1513 world map and the Book of the Sea, a book with detailed information on early navigational techniques as well as relatively accurate charts for their time, describing the ports and cities of the Mediterranean Sea.

Vasco Núñz de Balboa first sees what will become known as the Pacific Ocean.

The earliest printed textbook for midwifes was written by Eucharius Rösslin (d.1526?) of Worms. First published in Germany, Die Rosengarten was dedicated to Princess Katherine of Saxony and was granted a copyright by Emperor Maximilian in 1513. The book was an immediate success. It then appeared in English in 1540 as The Birth of Mankind. By the mid-16th century, it had been translated into all the main European languages and had gone through numerous editions. It survived 40 editions, being used as late as 1730.

Painting by Leonardo da Vinci: Saint John the Baptist, an oil painting on walnut wood. Likely to have been completed between 1513 and 1516, it is believed to be his final painting. Its original size was 69 by 57 centimetres (27 in × 22 in). The painting is in the collection of the Louvre. In November 2022, it was loaned to Louvre Abu Dhabi for two years as part of the museum's fifth anniversary. The work depicts the figure of John the Baptist in isolation through the use of chiaroscuro, with the figure appearing to emerge from the shadowy background. The saint is dressed in furs, has long curly hair and is smiling in an enigmatic manner reminiscent of Leonardo's famous Mona Lisa. He holds a reed cross in his left hand, while his right hand points up toward heaven, similar to the figure of Saint Anne in Leonardo's Burlington House Cartoon. According to Frank Zöllner, Leonardo's use of sfumato "conveys the religious content of the picture", with the "gentle shadows [imbuing] the subject's skin tones with a very soft, delicate appearance, almost androgynous in its effect".

Engraving by Albrecht Dürer: Melancolia I a large 1514 engraving. Its central subject is an enigmatic and gloomy winged female figure thought to be a personification of melancholia — melancholy. Holding her head in her hand, she stares past the busy scene in front of her. The area is strewn with symbols and tools associated with craft and carpentry, including an hourglass, weighing scales, a hand plane, a claw hammer, and a saw. Other objects relate to alchemy, geometry or numerology. Behind the figure is a structure with an embedded magic square, and a ladder leading beyond the frame. The sky contains a rainbow, a comet or planet, and a bat-like creature bearing the text that has become the print's title. Dürer's engraving is one of the most well-known extant old master prints, but, despite a vast art-historical literature, it has resisted any definitive interpretation. Dürer may have associated melancholia with creative activity; the woman may be a representation of a Muse, awaiting inspiration but fearful that it will not return. As such, Dürer may have intended the print as a veiled self-portrait. Other art historians see the figure as pondering the nature of beauty or the value of artistic creativity in light of rationalism, or as a purposely obscure work that highlights the limitations of allegorical or symbolic art.

Raphael's friend, courtier Giovanbattista Branconio dell'Aquila, becomes the personal keeper of Hanno, the white elephant brought to Rome in 1514, as a gift by King Manuel I of Portugal to Pope Leo X (born Giovanni de' Medici) at his coronation.

Johannes Werner publishes his translation of Ptolemy's Geography, Nova Translatio Primi Libri Geographicae Cl. Ptolomaei, containing the Werner map projection and proposing use of the cross-staff for marine navigation.

Painting by Leonardo da Vinci: The Virgin and Child with Saint Anne, an unfinished oil painting, dated to c. 1501–1519. It depicts Saint Anne, her daughter the Virgin Mary and the infant Jesus. Christ is shown grappling with a sacrificial lamb symbolizing his Passion as the Virgin tries to restrain him. The painting was commissioned as the high altarpiece for the Church of Santissima Annunziata in Florence and its theme had long preoccupied Leonardo. Leonardo's painting is at once both pleasing, calm yet confusing upon closer examination. The composition of the three figures is fairly tight, with the Virgin Mary clearly interacting with the infant Jesus. Upon closer examination of their positioning it is apparent that Mary is sitting on Saint Anne's lap. It is unclear what meaning this could have and what meaning Leonardo intended to project with that pose. There is no clear parallel in other works of art and women sitting in each other's lap are not a clear cultural or traditional reference that the viewer can relate to.

Painting by Raphael: Portrait of Baldassare Castiglione, Count of Casatico, an Italian courtier, diplomat, soldier and a prominent Renaissance author. Castiglione wrote Il Cortegiano or The Book of the Courtier, a courtesy book dealing with questions of the etiquette and morality of the courtier. It was very influential in 16th-century European court circles.

The first Johannes Schöner Globe, a printed globe, was made. Two exemplars survive, one at the Historisches Museum in Frankfurt and the other at the Herzogin Anna Amalia Bibliothek, at Weimar. There can be little doubt that Schöner was familiar with the globe made in Nuremberg by Martin Behaim in 1492. An inscription across the northern part of America, says: "This part of the island has been discovered by order of the King of Castile". This is matched by another inscription off America's east coast: "The more southerly part of this island was discovered by order of the King of Portugal"; that is, America is called in both an island. A strait between the southern tip of America and the land to the south can be found on Schöner's globe before its "official discovery" by Ferdinand Magellan in 1520. The actual strait is at 53 degrees south, whereas in the 1515 globe its southernmost tip is shown at about 45 degrees south. Schöner accompanied his globe with an explanatory treatise, Luculentissima quaedam terrae totius descriptio ("A Most Lucid Description of All Lands"). It contained a description of America.

An Indian rhinoceros arrives in Lisbon, the first to be seen in Europe since Roman times.

Alterpiece sculpted and painted by, respectively, the Germans Nikolaus of Haguenau and Matthias Grünewald: Isenheim Alterpiece painted for the Monastery of St. Anthony in Issenheim near Colmar, which specialized in hospital work. The Antonine monks of the monastery were noted for their care of plague sufferers as well as for their treatment of skin diseases, such as ergotism. The image of the crucified Christ is pitted with plague-type sores, showing patients that Jesus understood and shared their afflictions. The veracity of the work's depictions of medical conditions was unusual in the history of European art.

Painting by Hieronymus Bosch: The Haywain Triptych, a panel painting by the Early Netherlandish painter Hieronymus Bosch, now in the Museo del Prado, Madrid, Spain. A date of around 1516 has been established by means of dendrochronological research. The central panel, signed "Jheronimus Bosch", measures 135 cm × 200 cm (53 in × 79 in) and the wings measure 147 cm × 66 cm (58 in × 26 in). The outside shutters feature a version of Bosch's The Wayfarer. The painting was part of a group of six acquired by King Philip II of Spain in 1570, and shipped to El Escorial four years later. It was later sold to the Marquis of Salamanca, and divided into three paintings. In 1848, the central panel was bought by Isabella II of Spain and brought to Aranjuez, the right one was returned to Escorial and the left went to the Prado. The triptych was finally recomposed in 1914 in the latter museum.

The fall of the Nantan meteorite is possibly observed near the city of Nantan, Nandan County, Guangxi (China).

Painting by Sebastiano del Piombo: The Raising of Lazarus, a large altarpiece of 1517–1519 by the Italian High Renaissance artist Sebastiano del Piombo, for which Michelangelo supplied drawings for some figures. Intended for Narbonne Cathedral in France, it is now normally in Room 18 of the National Gallery in London, where it is "NG1", the first painting catalogued at the founding of the gallery in 1824. It was commissioned by Cardinal Giulio de' Medici, then Archbishop of Narbonne and later Pope Clement VII (r. 1523–24), in what was effectively a contest engineered by Michelangelo, using Sebastiano as "a kind of deputy", or "cat's paw", in a rivalry between the two and Raphael, whose Transfiguration (now in the Vatican Pinacoteca) is the same size of 381 cm × 299 cm (150 in × 118 in) and was commissioned for the same cathedral.

Martin Luther publishes his Ninety-five Theses or Disputation on the Power and Efficacy of Indulgences, a list of propositions for an academic disputation. This work is retrospectively considered to have launched the Protestant Reformation and the birth of Protestantism, despite various proto-Protestant groups having existed previously. It detailed Luther's opposition to what he saw as the Roman Catholic Church's abuse and corruption by Catholic clergy, who were selling plenary indulgences, which were certificates supposed to reduce the temporal punishment in purgatory for sins committed by the purchasers or their loved ones.

Ottoman Turks defeat the Mamluks of Egypt and take control of Egypt and the Arabian Peninsula.

A third epidemic of sweating sickness in England hits Oxford and Cambridge.

German surgeon Hans von Gersdorff publishes his Feldbuch der Wundarzney ("Field book of surgery").

Painting by Titian: The Assumption of the Virgin or Frari Assumption, popularly known as the Assunta, is completed. It remains in the position it was designed for, on the high altar of the Basilica di Santa Maria Gloriosa dei Frari or Frari church in Venice. It is the largest altarpiece in the city, with the figures well over life-size, necessitated by the large church, with a considerable distance between the altar and the congregation. It marked a new direction in Titian's style, that reflected his awareness of the developments in High Renaissance painting further south, in Florence and Rome, by artists including Raphael and Michelangelo. The agitated figures of the Apostles marked a break with the usual meditative stillness of saints in Venetian painting, in the tradition of Giovanni Bellini and others. It was perhaps originally rather shocking for the Venetian public, but soon recognised as a masterpiece that confirmed Titian's position as the leading artist in Venice, and one of the most important in all Italy, a rival to Michelangelo and Raphael.

Henricus Grammateus (also known as Henricus Scriptor, Heinrich Schreyber or Heinrich Schreiber)publishes Ayn neu Kunstlich Buech in Vienna, containing the earliest printed use of plus and minus signs for arithmetic. He also publishes Libellus de compositione regularum pro vasorum mensuratione. Deque arte ista tota theoreticae et practicae and a new musical temperament, which is now named after him, for the harpsichord. It was a precursor of the equal temperament.

Dancing plague, a case of dancing mania, breaks out in Strasbourg. Somewhere between 50 and 400 people took to dancing for weeks. There are many theories behind the phenomenon, the most popular being stress-induced mass hysteria, suggested by John Waller. Other theories include ergot and religious explanations. There is controversy concerning the number of deaths.

Leonardo da Vinci dies in Amboise, France, an event represented in (an 1818) painting by the French artist Jean-Auguste-Dominique Ingres, showing the Italian artist and inventor Leonardo da Vinci dying, with Francis I of France holding his head. It was commissioned by Pierre Louis Jean Casimir de Blacas, the French ambassador in Rome, and is now in the Petit Palais in Paris.

Horses are brought to the New World by Hernán Cortéz.

The Miller Atlas, also known as Lopo Homem-Reineis Atlas, a richly illustrated Portuguese partial world atlas is published. It is a joint work of the cartographers Lopo Homem, Pedro Reinel and Jorge Reinel, and illustrated by miniaturist António de Holanda. The regions represented are the North Atlantic Ocean, Northern Europe, the Azores Archipelago, Madagascar, Horn of Africa, the Indian Ocean, Indonesia, the China Sea, the Moluccas, Brazil and the Mediterranean Sea. It was acquired by the librarian Bénigne Emmanuel Clement Miller in 1855 at a bookseller in Santarém, Portugal, hence the name Miller Atlas. In 1897, his widow sold it to the National Library of France, where it has stayed ever since.

A pandemic spreads from the Greater Antilles into Central America, and perhaps as far as Peru, killing much of the indigenous populations in these areas.